rs144411158

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PVS1PP3PP5_Very_Strong

The NM_017565.4(FAM20A):c.406C>T(p.Arg136*) variant causes a stop gained, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000601 in 1,613,968 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000056 ( 0 hom. )

Consequence

FAM20A
NM_017565.4 stop_gained, splice_region

Scores

Splicing: ADA: 0.9836

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 2.08

Publications

12 publications found

Variant links:

Genes affected

FAM20A (HGNC:23015): (FAM20A golgi associated secretory pathway pseudokinase) This locus encodes a protein that is likely secreted and may function in hematopoiesis. A mutation at this locus has been associated with amelogenesis imperfecta and gingival hyperplasia syndrome. Alternatively spliced transcript variants have been identified. [provided by RefSeq, Aug 2011]

FAM20A Gene-Disease associations (from GenCC):

amelogenesis imperfecta type 1G
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P, Ambry Genetics

FAM20A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 17 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

PP5

Variant 17-68555742-G-A is Pathogenic according to our data. Variant chr17-68555742-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 30879.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM20A	NM_017565.4 link	c.406C>T	p.Arg136*	stop_gained, splice_region_variant	Exon 2 of 11	ENST00000592554.2	NP_060035.2	Q96MK3L8B8N7Q8IYA5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAM20A	ENST00000592554.2 link	c.406C>T	p.Arg136*	stop_gained, splice_region_variant	Exon 2 of 11	1	NM_017565.4	ENSP00000468308.1		Q96MK3

Frequencies

GnomAD3 genomes

AF:

0.0000920

AC:

AN:

152108

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000266

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000438

AC:

AN:

251298

AF XY:

0.0000515

show subpopulations

Gnomad AFR exome

AF:

0.000431

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000561

AC:

AN:

1461742

Hom.:

Cov.:

AF XY:

0.0000550

AC XY:

AN XY:

727164

show subpopulations

African (AFR)

AF:

0.000568

AC:

AN:

33480

American (AMR)

AF:

0.0000671

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000580

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5640

European-Non Finnish (NFE)

AF:

0.0000432

AC:

AN:

1112008

Other (OTH)

AF:

0.0000994

AC:

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000985

AC:

AN:

152226

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74410

show subpopulations

African (AFR)

AF:

0.000289

AC:

AN:

41522

American (AMR)

AF:

0.00

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.000208

AC:

AN:

4810

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68022

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.518

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000491

Hom.:

Bravo

AF:

0.000102

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000412

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

May 11, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Arg136*) in the FAM20A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FAM20A are known to be pathogenic (PMID: 21990045, 23434854). This variant is present in population databases (rs144411158, gnomAD 0.04%). This premature translational stop signal has been observed in individual(s) with amelogenesis imperfecta and/or enamel-renal syndrome (PMID: 21549343, 23434854, 28086997). ClinVar contains an entry for this variant (Variation ID: 30879). For these reasons, this variant has been classified as Pathogenic. -

Sep 27, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 28086997, 18597613, 28694781, 23468644, 21549343, 23434854) -

Amelogenesis imperfecta type 1G

Pathogenic:2

Feb 09, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 01, 2012

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.60

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Uncertain

0.88

PhyloP100

2.1

Vest4

0.32

GERP RS

5.8

Mutation Taster

=9/191

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.98

dbscSNV1_RF

Pathogenic

0.84

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

rs144411158

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over